There is a wealth of information implicating cumulative cellular injury inflicted by reactive oxygen species and heavy metal toxicity in neuronal damage and neurodegenerative diseases. Cells have evolved various endogenous antioxidant defenses to afford protection from oxidative injury or to reduce oxidative stress. Selenium is an essential contributor to these defenses, as it is required for the activity of a family of antioxidant enzymes that protect cells against the damaging products of normal oxygen metabolism. Selenium has also long been known to function as an antidote to toxicity of heavy metals. Selenoprotein P has recently been shown to function as a selenium delivery protein to brain, providing a source of this essential trace element for synthesis of other selenoproteins when selenium is deficient in the diet. Targeted disruption of the selenoprotein P gene results in neurological dysfunction. The overall goals of this study are to investigate the selenium delivery function of selenoprotein P in cells of neuronal origin, and to identify the crucial target selenoproteins which function in protection from oxidant and heavy metal induced damage, and which presumably explain the neurological effects of selenoprotein P gene disruption. These goals will be addressed through the following specific aims: ? 1. Investigate the means by which selenoprotein P serves as a Se donor to cells in culture, including interactions at the cell membrane and within the cell. ? 2. Investigate the expression levels and subcellular localization of specific selenoproteins, and whether localization or expression levels or patterns change in response to oxidative damage. Investigate the expression of specific selenoproteins in tissue sections from different brain regions in mice, and the changes in the expression levels or localization in response to GSH depletion or ischemia/reperfusion injury. ? 3. Identify the specific selenoproteins in neuronal cells responsible for protection from oxidative damage, resulting from either reactive oxygen species production or accumulation, or heavy metal induced damage. ? 4. Investigate expression of selenoproteins in brain sections obtained at autopsy from a cohort of Japanese men diagnosed with Alzheimer's or Parkinson's disease, vascular dementia, other neurological damage or with no evidence of neurodegenerative disease. ? ?
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